Methods, systems and devices for optical stimulation of target cells using an optical transmission element

ABSTRACT

Stimulation of target cells using light, e.g., in vivo, is implemented using a variety of methods and devices. In one such device, target cells are stimulated using an implantable device. The device includes a light source for producing light from electrical power. An optical transmission element is made from a material that is substantially transparent to the light from the light source. This transmission element substantially encases the light source at a proximal end. The transmission element delivers light from the light source to a distal end. The shape and size of the transmission element facilitates implanting of the element within a patient. A fixation portion physically couples to the optical transmission element and secures the device to the patient. A heat dissipation portion removes heat from the near optical transmission element and the light source and dissipates the removed heat through the fixation portion.

RELATED PATENT DOCUMENTS

This patent document claims the benefit, under 35 U.S.C. §119(e), ofU.S. Provisional Patent Application Ser. No. 61/132,162 filed on Jun.17, 2008, which is fully incorporated herein by reference.

This application also relates to U.S. patent application Ser. No.11/651,422, filed Jan. 9, 2007, which is a continuation-in-part of U.S.patent application Ser. No. 11/459,636 filed on Jul. 24, 2006 andentitled “Light-Activated Cation Channel and Uses Thereof,” and to U.S.Provisional Application No. 60/701,799 filed Jul. 22, 2005. Each ofthese patent documents is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to systems and approaches forstimulating target cells, and more particularly to using optics tostimulate the target cells using an optical transmission element.

BACKGROUND

The stimulation of various cells of the body has been used to produce anumber of beneficial effects. One method of stimulation involves the useof electrodes to introduce an externally generated signal into cells.One problem faced by electrode-based brain stimulation techniques is thedistributed nature of neurons responsible for a given mental process.Conversely, different types of neurons reside close to one another suchthat only certain cells in a given region of the brain are activatedwhile performing a specific task. Alternatively stated, not only doheterogeneous nerve tracts move in parallel through tight spatialconfines, but the cell bodies themselves may exist in mixed, sparselyembedded configurations. This distributed manner of processing seems todefy the best attempts to understand canonical order within the centralnervous system (CNS), and makes neuromodulation a difficult therapeuticendeavor. This architecture of the brain poses a problem forelectrode-based stimulation because electrodes are relativelyindiscriminate with regards to the underlying physiology of the neuronsthat they stimulate. Instead, physical proximity of the electrode polesto the neuron is often the single largest determining factor as to whichneurons will be stimulated. Accordingly, it is generally not feasible toabsolutely restrict stimulation to a single class of neuron usingelectrodes.

Another issue with the use of electrodes for stimulation is that becauseelectrode placement dictates which neurons will be stimulated,mechanical stability is frequently inadequate, and results in leadmigration of the electrodes from the targeted area. Moreover, after aperiod of time within the body, electrode leads frequently becomeencapsulated with glial cells, raising the effective electricalresistance of the electrodes, and hence the electrical power deliveryrequired to reach targeted cells. Compensatory increases in voltage,frequency or pulse width, however, may spread the electrical current andincrease the unintended stimulation of additional cells.

Another method of stimulus uses photosensitive bio-molecular structuresto stimulate target cells in response to light. For instance, lightactivated proteins can be used to control the flow of ions through cellmembranes. By facilitating or inhibiting the flow of positive ornegative ions through cell membranes, the cell can be brieflydepolarized, depolarized and maintained in that state, orhyperpolarized. Neurons are an example of a type of cell that uses theelectrical currents created by depolarization to generate communicationsignals (i.e., nerve impulses). Other electrically excitable cellsinclude skeletal muscle, cardiac muscle, and endocrine cells. Neuronsuse rapid depolarization to transmit signals throughout the body and forvarious purposes, such as motor control (e.g., muscle contractions),sensory responses (e.g., touch, hearing, and other senses) andcomputational functions (e.g., brain functions). Thus, the control ofthe depolarization of cells can be beneficial for a number of differentpurposes, including (but not limited to) psychological therapy, musclecontrol and sensory functions.

Optical-based stimulus, however, often involves the generation of heatwhich can be passed to cells of the body. Heat affects both the functionand the physical viability of many cell types and may cause cell damageor death. In brain tissue, for example, the threshold for cell death isgenerally about fifty-six degrees Celsius maintained for one second, orfifty-two degrees for longer periods of time. Tissues held aboveforty-three degrees Celsius for more than an hour or so may have theirphysiological processes (including cell division) interrupted. Even moresubtle elevations in temperature, above the normal thirty-seven degreesCelsius, are thought to change metabolic processes including affectingspontaneous firing rate.

SUMMARY

The claimed invention is directed to photosensitive bio-molecularstructures and related methods. The present invention is exemplified ina number of implementations and applications, some of which aresummarized below.

An embodiment of the present invention is directed towards an opticaldelivery device for delivering light to a patient. The device includes alight source for producing light from electrical power. An opticaltransmission element is made from a material that is substantiallytransparent to the light from the light source. This transmissionelement substantially encases the light source at a proximal end. Thetransmission element delivers light from the light source to a distalend. The shape and size of the transmission element facilitatesimplanting of the element within a patient. A fixation portionphysically couples to the optical transmission element and secures thedevice to the patient. A heat dissipation portion removes heat from thenear optical transmission element and the light source and dissipatesthe removed heat through the fixation portion.

Consistent with an embodiment of the present invention, a method isimplemented stimulating target cells in vivo. Light-activated ionchannels are engineered in one or more in vivo target cells. A device issurgically implanted. The device includes a light source for producinglight from electrical power, an optical transmission element made from amaterial that is substantially transparent to the light from the lightsource, the material having an elongated shape that substantiallyencases the light source at a proximal end and that is for deliveringthe light from the light source to a distal end, a fixation portionphysically coupled to the optical transmission element for attachment tothe patient, and a heat dissipation portion to remove heat from near theoptical coupling of the optical transmission element and the lightsource and to dissipate the removed heat through the fixation portion.After implantation, the light source is activated to stimulate thetarget cells.

According to one example embodiment of the present invention, animplantable arrangement is implemented having a light-generation devicefor generating light. The arrangement also has a biological portion thatmodifies target cells for stimulation in response to light generated bythe light-generation means in vivo. Stimulation may be manifested aseither upregulation (e.g., increased neuronal firing activity), ordownregulation (e.g., neuronal hyperpolarization, or alternatively,chronic depolarization) of activity at the target.

According to another example embodiment of the present invention, amethod is implemented for stimulating target cells using photosensitiveproteins that bind with the target cells. The method includes a step ofimplanting the photosensitive proteins and a light generating devicenear the target cells. The light generating device is activated and thephotosensitive protein stimulates the target cells in response to thegenerated light.

Applications include those associated with any population ofelectrically-excitable cells, including neurons, skeletal, cardiac, andsmooth muscle cells, and insulin-secreting pancreatic beta cells. Majordiseases with altered excitation-effector coupling include heartfailure, muscular dystrophies, diabetes, pain, cerebral palsy,paralysis, depression, and schizophrenia. Accordingly, the presentinvention has utility in the treatment of a wide spectrum of medicalconditions, from Parkinson's disease and brain injuries to cardiacdysrhythmias, to diabetes, and muscle spasm.

According to other example embodiments of the present invention, methodsfor generating an inhibitory neuron-current flow involve, in a neuron,engineering a protein that responds to light by producing an inhibitorycurrent to dissuade depolarization of the neuron. In one such method,the protein is halorhodopsin-based and in another method the protein isan inhibitory protein that uses an endogenous cofactor.

According to another example embodiment of the present invention, amethod for controlling action potential of a neuron involves thefollowing step: engineering a first light responsive protein in theneuron; producing, in response to light, an inhibitory current in theneuron and from the first light responsive protein; engineering a secondlight responsive protein in the neuron; and producing, in response tolight, an excitation current in the neuron from the second lightresponsive protein.

In another method for controlling a voltage level across a cell membraneof a cell, the method comprises: engineering a first light responsiveprotein in the cell; measuring the voltage level across the cellmembrane; and producing, in response to light of a first wavelength andusing the first light responsive protein, a current across the cellmembrane that is responsive to the measured voltage level.

The above summary of the present invention is not intended to describeeach illustrated embodiment or every implementation of the presentinvention. The figures and detailed description that follow moreparticularly exemplify these embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be more completely understood in consideration of thedetailed description of various embodiments of the invention thatfollows in connection with the accompanying drawings, in which:

FIG. 1A depicts an implantable device as implemented for deep-brainneuromodulation, consistent with an embodiment of the present invention;

FIG. 1B illustrates a detailed view of a possible implantationorientation and location, consistent with embodiments of the presentinvention;

FIG. 2A depicts an elongate structure integrally coupled to an LEDelement for efficiently delivering light to a target location,consistent with an embodiment of the present invention;

FIG. 2B depicts an embodiment of the present invention in which elongatestructure is integrally formed to the electronic portions;

FIG. 2C illustrates an embodiment of the present invention in which, atthe proximal end of the device, a heat sink/mounting base surrounds anegative lead and a positive lead;

FIGS. 3A and 3B depict an elongate structure for controlling light byrotational movement of the elongate structure, consistent with anembodiment of the present invention;

FIGS. 3C and 3D show movement of a light delivery structure within afixation portion, consistent with an embodiment of the presentinvention; and

FIG. 4 shows a light delivery structure, consistent with an embodimentof the present invention.

While the invention is amenable to various modifications and alternativeforms, specifics thereof have been shown by way of example in thedrawings and will be described in detail. It should be understood,however, that the intention is not to limit the invention to theparticular embodiments described. On the contrary, the intention is tocover all modifications, equivalents, and alternatives falling withinthe spirit and scope of the invention.

DETAILED DESCRIPTION

The present invention is believed to be useful for facilitatingpractical application of a variety of photosensitive bio-molecularstructures, and the invention has been found to be particularly suitedfor use in arrangements and methods dealing with cellular membranevoltage control and stimulation, including those using an opticaltransmission element designed for implantation. While the presentinvention is not necessarily limited to such applications, variousaspects of the invention may be appreciated through a discussion ofvarious examples using this context.

An embodiment of the present invention is directed towards an opticaldelivery device for delivering light to a patient. The device includes alight source for producing light from electrical power. An opticaltransmission element is made from a material that is substantiallytransparent to the light from the light source. This transmissionelement substantially encases the light source at a proximal end. Thetransmission element delivers light from the light source to a distalend. The shape and size of the transmission element facilitatesimplanting of the element within a patient. A fixation portionphysically couples to the optical transmission element and secures thedevice to the patient. A heat dissipation portion removes heat from thenear optical transmission element and the light source and dissipatesthe removed heat through the fixation portion.

Another embodiment of the present invention is directed toward atransmission element is made from a material that is substantiallytransparent to the light from the light source. This transmissionelement substantially encases the light source at a proximal end. Thetransmission element delivers light from the light source to a distalend. The shape and size of the transmission element facilitatesimplanting of the element within a patient. In certain implementations,the transmission element can be designed for fixation to the person oranimal under test/treatment.

Light can be delivered to targeted locations by optical fiber carryinglight from an external source, or by implanted light-emitting diode(LED). An optical fiber approach to optogenetic stimulation, iswell-suited to precise, deep-brain implantation, as the cylindricalshape and narrow-diameter (for example 20 microns) permit stereotacticinsertion with minimal trauma to tissue, while assuring focused deliveryof light at the end of the fiber. Such an optical fiber approach uses abulky, high-power-consumption, heat-generating light source (for examplea Xenon lamp with an optical coupling to the fiber). Heat is generatednot only by the light generation process, but also by the opticalcoupling, e.g., where light that fails to cross the interfaces ofdifferent components along the light path generates heat. Yet otherpotential heat sources are electrical circuit elements, which canprovide control of the light source.

LED approaches to optogenetic stimulation, while often more compact (intotal) and more power efficient than a Xenon lamp with optical fibercoupling, are often less compact at the point of light output, and alsogenerate significant heat close to the source of the output.Additionally, conventional LEDs lack the smooth linear configurationthat lends optical fiber implantation to the stereotactic surgicalapproach. Thus, the implantation of LEDs can be more intrusive andphysically damaging to tissues. LEDs may be optically coupled to opticalfibers and thereby physically displacing the principal area of heatgeneration, and the principal area of light delivery. However, the lightcoupling process between the LED and optical fiber is inefficient,causing substantial heat loss due to the reflective and refractiveproperties of the interfaces between LED lens and optical fiber.

Accordingly, specific implementations can be particularly useful formitigating unwanted heat from an implanted light source. One suchimplementation involves an optical delivery device that providesefficient opto-coupling between a relatively low-power optical sourceand a transmission element designed for implantation and delivery oflight to target cells. The transmission element is designed to providetotal internal reflection of light when implanted within a patient.Total internal reflection occurs when the angle of incidence of thelight is sufficient relative to the critical angle above whichreflection occurs.

In an embodiment of the present invention, the transmission element isdesigned to be maintained in a relatively rigid or unbending physicalshape. This can be particularly useful for designing the transmissionelement with respect to the total internal reflection of light whenimplanted within a patient. For instance, fiber optic cable is oftenspecifically designed to allow for a maximum bending angle. This bendingangle is determined as a function of the optical properties of the coreand the surrounding cladding. Reducing or eliminating such bending fromthe transmission element relaxes the design constraints, e.g., byeffectively increasing the range of acceptable angles of incidence ofthe light.

Some implementations use a transmission element that has a desiredcritical angle that is defined by an interface between the transmissionelement and properties of internal body components such as body fluidsor tissue. In this manner, the internal body components function like anexternal cladding-type layer during the delivery of light to a targetlocation.

Embodiments of the present invention relate to the design of thetransmission element. A variety of different shapes are possible for theshaft of the transmission element, e.g., cylindrical, conical orflat/rectangular. Moreover, the end of the transmission element forplacement near the target location can be designed to further controlthe delivery of light. This can include, for instance, focusing lighttoward a tightly controlled area or dispersing light over a large area.

Aspects of the present invention also relate to methods and devices forheat dissipation. For instance, a heat-conductive section can bethermally coupled to sources of heat. The sources of heat may includethe optical light source, control electronics, power source or externaltemperature source, such as environmental sources of heat. Theheat-conductive section can be designed to dissipate heat away from theinsertion point of the transmission element. This can includedissipation of heat into the air, the vascularized bone and/or softtissue. Thermally-insulating material can be placed between thethermally-conductive (heat-sink) section and the insertion point,thereby mitigating heating of internal tissue.

The heat-conductive section can be designed with sufficient surface areato dissipate the required amount of heat. The heat-conductive sectioncan be designed from a number of different conductive materialsincluding, but not limited to, thermally-conductive metals like copper.The surface area of the heat-conductive section can be designed withporous material, fins or other aspects that help increase the surfacearea. In a particular implementation, the heat-conductive section isinsulated from external environmental heat sources. The heat is therebysubstantially all dissipated into the vascularized bone and/or softtissue. This can be particularly useful for allowing use of the devicein varying environments and external temperatures.

According to one embodiment of the present invention, a thermal sensoris used to monitor the temperature near the insertion point. In responseto the temperature reading, the device can emit a warning signal and/ormodify operation of the light source. For instance, the device candisable the light source in response to the temperature exceeding apredetermined threshold level.

In some embodiments of the present invention, a control circuit and apower source are included as components of the device. These componentscan be designed for external placement on the patient. For instance, abattery and microcontroller is placed within, or as part of, a mountingbase that is affixed to the patient, e.g., to the skull for neuralstimulation. In certain implementations, one or more of these componentsare placed away from the insertion point. Electrical connections providecontrol over the light source. Thermal-insulation can be introducedbetween these components and the insertion point to mitigate heattransfer to the insertion point.

In certain implementations involving a rigid transmission element, thetransmission element has a set length that corresponds to an approximateinsertion depth for delivery of light to a target location. Eachpatient, however, can have a different morphology and/or desired targetlocation. In one instance, the transmission element can be individuallymodified for each procedure. This can be accomplished by removing asection of the transmission element to obtain the desired length. Inanother implementation, an adjustable portion of the mounting baseallows for control of the depth of the transmission element.

Certain embodiments of the present invention relate to allowed movementof the transmission element relative to the mounting base of the system.For instance, the mounting base allows the transmission element tofreely move in a lateral direction. Once the transmission element isproperly located, the mounting base secures the transmission element toprevent future movement. The transmission element is secured using aclamping mechanism, a cementing agent or other suitable fixationmechanisms. Another potential use of allowed movement of thetransmission element relative to the mounting base of the system relatesto further control of the light delivery location. The tip of thetransmission element can be designed to direct light at an anglerelative to the long-axis of the transmission element. By allowingrotational movement of such a transmission element, the light-stimuluslocation can be adjusted. Once the desired orientation is determined,e.g., by testing the effectiveness of various orientations, thetransmission element can be fixed to prevent further movement.

While not so limited, embodiments of the present invention areparticularly well-suited for use with one or more of the followingexample embodiments directed towards light responsive proteins.

Consistent with one example embodiment of the present invention, alight-responsive protein is engineered in a cell. The protein affects aflow of ions across the cell membrane in response to light. This changein ion flow creates a corresponding change in the electrical propertiesof the cells including, for example, the voltage and current flow acrossthe cell membrane. In one instance, the protein functions in vivo usingan endogenous cofactor to modify ion flow across the cell membrane. Inanother instance, the protein changes the voltage across the cellmembrane so as to dissuade action potential firing in the cell. In yetanother instance, the protein is capable of changing the electricalproperties of the cell within several milliseconds of the light beingintroduced. For further details on delivery of such proteins, referencemay be made to U.S. patent application Ser. No. 11/459,636 filed on Jul.24, 2006 and entitled “Light-Activated Cation Channel and Uses Thereof”,which is fully incorporated herein by reference.

Consistent with a more specific example embodiment of the presentinvention a protein, NpHR, from Natronomonas pharaonis is used fortemporally-precise optical inhibition of neural activity. NpHR allowsfor selective inhibition of single action potentials within rapid spiketrains and sustained blockade of spiking over many minutes. The actionspectrum of NpHR is strongly red-shifted relative to ChR2 but operatesat similar light power, and NpHR functions in mammals without exogenouscofactors. In one instance, both NpHR and ChR2 can be expressed in thetarget cells. Likewise, NpHR and ChR2 can be targeted to C. elegansmuscle and cholinergic motoneurons to control locomotionbidirectionally. In this regard, NpHR and ChR2 form an optogeneticsystem for multimodal, high-speed, genetically-targeted, all-opticalinterrogation of living neural circuits.

Certain aspects of the present invention are based on the identificationand development of an archaeal light-driven chloride pump, such ashalorhodopsin (NpHR), from Natronomonas pharaonis, fortemporally-precise optical inhibition of neural activity. The pumpallows both knockout of single action potentials within rapid spiketrains and sustained blockade of spiking over many minutes, and itoperates at similar light power compared to ChR2 but with a stronglyred-shifted action spectrum. The NpHR pump also functions in mammalswithout exogenous cofactors.

According to other example embodiments of the present invention, methodsfor generating an inhibitory neuron-current flow involve, in a neuron,engineering a protein that responds to light by producing an inhibitorycurrent to dissuade depolarization of the neuron. In one such method,the protein is halorhodopsin-based and in another method the protein isan inhibitory protein that uses an endogenous cofactor.

In another example embodiment, a method for controlling action potentialof a neuron involves the following steps: engineering a first lightresponsive protein in the neuron; producing, in response to light, aninhibitory current in the neuron and from the first light responsiveprotein; engineering a second light responsive protein in the neuron;and producing, in response to light, an excitation current in the neuronfrom the second light responsive protein.

In another method for controlling a voltage level across a cell membraneof a cell, the method includes: engineering a first light responsiveprotein in the cell; measuring or inferring the voltage level across thecell membrane (e.g., using voltage sensitive dyes or measurements ofbrain activity); and producing, in response to light of a firstwavelength and using the first light responsive protein, a currentacross the cell membrane that is responsive to the measured or inferredvoltage level.

Another aspect of the present invention is directed to a system forcontrolling an action potential of a neuron in vivo. The system includesa delivery device, a light source, and a control device. The deliverydevice introduces a light responsive protein to the neuron, with thelight responsive protein producing an inhibitory current. The lightsource generates light for stimulating the light responsive protein, andthe control device controls the generation of light by the light source.

In more detailed embodiments, such a system is further adapted such thatthe delivery device introduces the light responsive protein by one oftransfection, transduction and microinjection, and/or such that thelight source introduces light to the neuron via one of an implantablelight generator and fiber-optics.

Another aspect of the present invention is directed to a method fortreatment of a disorder. The method targets a group of neuronsassociated with the disorder; and in this group, the method includesengineering an inhibitory proteins that use an endogenous cofactor torespond to light by producing an inhibitory current to dissuadedepolarization of the neurons, and exposing the neurons to light,thereby dissuading depolarization of the neurons.

According to yet another aspect of the present invention is directed toidentifying and developing an archaeal light-driven chloride pump, suchas halorhodopsin (NpHR), from Natronomonas pharaonis, fortemporally-precise optical inhibition of neural activity. The pumpallows both knockout of single action potentials within rapid spiketrains and sustained blockade of spiking over many minutes, and itoperates at similar light power compared to ChR2 but with a stronglyred-shifted action spectrum. The NpHR pump also functions in mammalswithout exogenous cofactors.

More detailed embodiments expand on such techniques. For instance,another aspect of the present invention co-expresses NpHR and ChR2 inthe species (e.g., a person or a mouse). Also, NpHR and ChR2 areintegrated with calcium imaging in acute mammalian brain slices forbidirectional optical modulation and readout of neural activity.Likewise, NpHR and ChR2 can be targeted to C. elegans muscle andcholinergic motoneurons to control locomotion bidirectionally. TogetherNpHR and ChR2 can be used as a complete and complementary opto-geneticsystem for multimodal, high-speed, genetically-targeted, all-opticalinterrogation of living neural circuits.

In addition to NpHR and ChR2, there are a number of channelrhodopsins,halorhodopsins, and microbial opsins that can be engineered to opticallyregulate ion flux or second messengers within cells. Various embodimentsof the invention include codon-optimized, mutated, truncated, fusionproteins, targeted versions, or otherwise modified versions of such ionoptical regulators. Thus, ChR2 and NpHR (e.g., GenBank accession numberis EF474018 for the ‘mammalianized’ NpHR sequence and EF474017 for the‘mammalianized’ ChR2(1-315) sequence) are used as representative of anumber of different embodiments. Discussions specifically identifyingChR2 and NpHR are not meant to limit the invention to such specificexamples of optical regulators. For further details regarding the abovementioned sequences reference can be made to “Multimodal fast opticalinterrogation of neural circuitry” by Feng Zhang, et al, Nature (Apr. 5,2007) Vol. 446: pp. 633-639, which is fully incorporated herein byreference.

Consistent with a particular embodiment of the present invention, aprotein is introduced to one or more target cells. When introduced intoa cell, the protein changes the potential of the cell in response tolight having a certain frequency. This may result in a change in restingpotential that can be used to control (dissuade) action potentialfiring. In a specific example, the protein is a halorhodopsin that actsas a membrane pump for transferring charge across the cell membrane inresponse to light. Membrane pumps are energy transducers which useelectromagnetic or chemical bond energy for translocation of specificions across the membrane. For further information regardinghalorhodopsin membrane pumps reference can be made to “Halorhodopsin Isa Light-driven Chloride Pump” by Brigitte Schobert, et al, The Journalof Biological Chemistry Vol. 257, No. 17. Sep. 10, 1982, pp.10306-10313, which is fully incorporated herein by reference.

The protein dissuades firing of the action potential by moving thepotential of the cell away from the action potential trigger level forthe cell. In many neurons, this means that the protein increases thenegative voltage seen across the cell membrane. In a specific instance,the protein acts as a chloride ion pump that actively transfersnegatively charged chloride ions into the cell. In this manner, theprotein generates an inhibitory current across the cell membrane. Morespecifically, the protein responds to light by lowering the voltageacross the cell thereby decreasing the probability that an actionpotential or depolarization will occur.

As used herein, stimulation of a target cell is generally used todescribe modification of properties of the cell. For instance, thestimulus of a target cell may result in a change in the properties ofthe cell membrane that can lead to the depolarization or polarization ofthe target cell. In a particular instance, the target cell is a neuronand the stimulus affects the transmission of impulses by facilitating orinhibiting the generation of impulses by the neuron.

Turning now to the figures, FIG. 1A depicts an implantable device asimplemented for deep-brain neuromodulation, consistent with anembodiment of the present invention. FIG. 1A and the followingdiscussion specifically mention and discuss deep-brain neuromodulation;however, the invention is not so limited. The system of FIG. 1A includeselongate transmission elements 104 and 106. Fixation bases 114 and 112fix the transmission elements 104 and 106, respectively, to the skull ofthe patient 102. Light source, such as LEDs, produces light that isdirected to target locations by transmission elements 104 and 106. Apulse-generator circuit 115, having a power source 116, generatescontrol pulses that cause the LEDs to produce light.

In a specific implementation, a surgeon implants flexible power/controlleads 113 and 115 under the skin. The battery 116 and pulse-generatorunit 115 are implanted separately from the LEDs 104 and 106, for exampleagainst the chest wall. Heat-sink/fixation base 112 surrounds theproximal portion of LED with elongate structure 106, whileheat-sink/fixation base 114 surrounds the proximal portion of LED withelongate structure 104. Implantation to sub-surface regions of the brainor body can be accomplished by pushing the device in a linear fashionfrom the external surface of the body part, toward the target, typicallyusing stereotactic devices and associated methods used for preciseplacement of instruments and implantable devices within the brain andbody. Commercially available devices for stereotactic placement ofimplantable include the “Universal Tool” customization feature on the“Stealth Station” series of computerized image guidance systems by theSurgical Navigation Technologies division (Broomfield, Colo.) ofMedtronic Inc. (Minneapolis, Minn.).

By integrally forming an elongate structure with the electronic elementsof an LED, the device becomes readily implantable in a precise targetedmanner, and is spatially fixable. The primary source of heat isphysically displaced from sensitive underlying tissues such as braincells, such that damage to cells is mitigated. For instance, the heatsink at the proximal end captures and diffuses heat into vascularizedbone and soft tissue that is less heat sensitive than the target cellsor interposed tissue.

FIG. 1B illustrates a detailed view of a possible implantationorientation and location, consistent with embodiments of the presentinvention. A light source, such as an LED, couples to an elongatestructure 125, which is implanted in brain 129. Heat-sink/fixation base140 attaches to the proximal portion of the light source and elongatestructure, surrounding the point of electricity-to-light conversion.Heat-sink/fixation base 130 may be adhered to skull 132, for examplewith methacrylate, or sutured or otherwise affixed to tissue 133overlying or underlying bone. The distal end of the combination of LEDand elongate structure 125 is placed so as to illuminate the biologicalportion 127, which may be described as an anatomical target opticalstimulation. In this illustration biological portion 127 is Brodmann'sArea 25 of the brain. Other potential targeted biological portionsdepend upon the specific experimental or therapeutic application and caninclude, but are not limited to, the subthalamic nucleus, the globuspallidus interna, the dentate gyms, the CA-1 field of the hippocampus,the medial hypothalamic area and the lateral hypothalamic area.

FIG. 2A depicts an elongate structure integrally coupled to an LEDelement for efficiently delivering light to a target location,consistent with an embodiment of the present invention. Elongatestructure 210 is depicted as a cylindrical to conical,linearly-extending, optically transparent or translucent object ofgenerally uniform internal consistency. Elongate structure 210 need notbe limited to any specific materials but can be implemented using glassor plastics, such as polycarbonate. Elongate structure 210 is tightlyformed to LED element 202, and the distal portions of negative electrode206 and positive electrode 204. Light 208 is emitted from diode 202 andtraverses elongate structure 210 along light beams 212 and 214. Thelight beams reflect upon the surface boundaries of elongate structure210. Assuming the angle of incidence of the light is sufficient relativeto the critical angle above which reflection occurs, the light isredirected internally to the elongate structure 210. A substantialportion of the light ultimately passes out of elongate structure 210 asbeams 216, which illuminate a target location 218, e.g., alight-sensitive cell, in a manner that modifies its activity.

FIG. 2B depicts an embodiment of the present invention in which elongatestructure 230 is integrally formed to the electronic portions, includingthe distal portions of positive lead 224 and negative lead 226 andinterposed diode element (not shown) and thus able to efficientlydeliver light to the biological portion, in this case, a neuron.Elongate structure 230 is a longitudinally tapering cylinder ofoptical-grade material such as glass or plastic. Blue light 228 isemitted within the proximal portion of elongate structure 230 aninternally reflects. The light leaves the distal end of elongatestructure 230 as blue light 236.

In a particular implementation, the target location 218 includes one ormore neural cells expressing an optically responsive ion channel or pumpsuch as ChR2. When pulses of blue light 236 falls upon ChR2-expressingneural cell 218, this cell exhibits an action potential with each pulse,and is thereby regulated by electrical input to leads 224 and 226.

FIG. 2C illustrates an embodiment of the present invention in which, atthe proximal end of the device, heat sink/mounting base 262 surroundsnegative lead 256 and positive lead 254. In a particular implementation,the diode element interposed between them (not shown) emits yellowlight. Elongate structure 260 is a longitudinally tapering cylinder ofoptical-grade material such as glass or plastic, which delivers light toneuron 265, which has been genetically modified to express NpHR. Whenyellow light is emitted from elongate structure 260 and falls uponneuron 265, this cell exhibits resistance to action potentials. Heatsink/mounting base 262 serves dual purposes as both a mass whichconducts and diffuses heat from near the site of light generation withinthe device, and as a base which can be affixed firmly to skull.

The LED designed with an integrally-formed elongate structure whichcorrelates to the dimensions of an optical fiber, for delivering lightto cells with light-activated ion channels to sub-surface regions of thebrain or body. The elongate structure (e.g., 104, 106, 125, 210, 230,260) can assume a smooth shape, for example a cylinder, taperingcylinder, cone, or flat elongate rectangular shape. Such lenses may bemade of a variety of clear or colored translucent materials includingpolycarbonate and glass. The lens is generally formed integrally andtightly fitting around the electronic elements including the diodeitself, for example, by high-pressure injection molding to remove allair interposed between lens material and diode element. The lensdiameter may vary depending upon the specific area that requiresillumination. For example, an elongate structure of 20 mm diameter(comparable with optical fibers previously used to deliver light to deepanatomical targets), is suited to the delivery of light to the cellbodies and/or axons of small clusters of neurons. Smaller diameterlenses (for example, 10 microns or less) may be more suited todelivering light to individual cells. Use of larger diameter lenses (forexample 1 mm×1 mm square lenses or 1 mm diameter cylindrical lenses) maybe useful for illuminating large swaths of targeted tissue. Smallerdiameter lenses tend to be more fragile than larger diameter lenses,however, depending upon the specific material used for its composition.

The transmission element or elongate structure may have optical focusingproperties, or may simply serve as a non-refractive transmission channelwhich physically separates the heat-generating light production portionfrom the heat-sensitive, optically-reactive target. The tip may be thesame diameter as the base of the structure, or it may be of differentdimensions.

The shape of the elongate structure may also be altered or improvedafter initial manufacture. For example, plastics or glass elongatestructures may be molded in an initial elongate shape, then drawn out tolong and thin dimensions, using methods and tools commonly used in theneuroscience laboratory for the ad-hoc creation of glass pipetteelectrodes for intracellular electrical recording. Using this method,glass cylinders are heated over a small area, and are then linearlystretched. At the proper length and reduced diameter, themicropipette/electrode glass is cut. This process and facilitatingdevices (which are commercially available) similarly serves the processof creating an elongate structure of the proper length and diameter,with the difference that a cylindrical lens with formed-in electronicelements (including the diode itself) replaces the glass cylinder usedfor making a microelectrode. This same process may be accomplished withplastic elongate structures, either by heating and drawing out as withglass, or by drawing out the plastic before it has cured.

The heat sink/mounting base (e.g., FIG. 1A: 112, 114; FIG. 1B: 130; FIG.2C: 262) serves dual purposes as both a mass which conducts and diffusesheat from near the site of light generation within the device, and as abase which can be affixed firmly to skull. This portion is typical atthe (proximal) base of the apparatus, surrounding the active poles anddiode portions of the device. This base may be sutured to tissue viaholes placed in the base, and may be cemented to the skull directly, forexample using a methacrylate-based compound.

FIGS. 3A and 3B depict an elongate structure for controlling light byrotational movement of the elongate structure, consistent with anembodiment of the present invention. Elongate structure 304 directslight toward the distal tip 306. The longitudinal direction 302 ofelongate structure 304 shows the general direction of travel for thelight. The distal tip 306 is designed to generally direct the light atan angle relative to the longitudinal direction 302. Thus, by rotatingthe elongate structure 304 around the distal tip (shown by arrows 310),the illumination pattern can be changed. This allows for fine-tuning ofthe effective delivery location for the optical stimulus. Duringsurgical implantation, the elongate structure 304 can be rotated. Atdifferent rotational positions, light can be provided to stimulatetarget cells. The effectiveness of the stimulation can be assessed andthe rotational position can be fixed accordingly. The assessment of theeffectiveness can be tailored toward the specific goal/treatment of theimplanted device.

The direction of travel for the light can be controlled using a varietyof optical-based principles, such as focusing or directing light usingrefraction or reflection caused by differing indices of refraction. Forinstance, FIG. 3A shows the tip 306 being other than perpendicular tothe longitudinal direction 302, such as perpendicular to direction 308.Moreover, the tip 306 can be constructed with a curve surface to furtherdirect the light. FIG. 3B shows a section 310, which can be made fromone or more materials having a different index of refraction relative tothat of the remainder of elongate structure 304. Various other directingoptions are possible including, but not limited to, reflective materialor an attached lens.

FIGS. 3C and 3D show movement of a light delivery structure within afixation portion, consistent with an embodiment of the presentinvention. Fixation portion 312 allows the elongate structure 304 torotate about the longitudinal axis. Alternatively, the elongatestructure 304 can also be allowed to move along the longitudinal axis asshown by the vertical arrows in FIG. 3D.

FIG. 4 shows a light delivery structure, consistent with an embodimentof the present invention. The light delivery structure includes a lumen404 that surrounds an opening 402. Optional outer layer 406 surroundslumen 404. In one implementation, the lumen is made from glass orplastic, such as a pipette or micropipette. The light is directedthrough the lumen as discussed herein. Outer layer 406 can help directthe light along the length of lumen 404. The lumen can be filled with amaterial, liquid or otherwise, to provide the desired opticalproperties. For instance, the lumen filling material can be used totransmit the optical light by either matching the refractive index ofthe lumen or having an index of refraction sufficiently different fromthat of the lumen to provide total internal reflection within the lumenfilling material.

FIG. 4 also depicts heat removal elements 408 and 410. These elementsare thermally coupled with the light source, which is substantiallyencased within the lumen 404 and/or the outer layer 406. Heat removalelement 408 is in thermal contact with the light source and dissipatesheat through thermally conductive strips 410. The thermally conductivestrips 410 can be connected to the fixation device or some otherstructure that acts as a heat sink 412. In a particular implementation,the material for lumen 404 has a high thermal resistance therebyallowing substantially all heat generated by the light source to bedissipated through the heat removal elements 408 and 410.

Further details of an example embodiment consistent with FIG. 4 includea commercially manufactured LED that is surrounded by index-matchingmaterial and contained within (or coupled to) a pipette or micropipettethat serves as a light delivery element. The distal end of the pipetteor micropipette is implanted at the neuronal target. The proximal end ofthis pipette contains the light production element. This lightproduction element may be a standard commercially availablelight-emitting diode package such as the SML0805-B1K-TR (LEDtronics Inc.Torrance, Calif.). Suitable micropipettes may be made in accordance withstandard laboratory procedures from glass tubing stock B200-156-10 and amicropipette puller machine model P1000, both available from SutterInstrument (Novato, Calif.). The internal or external surface of thepipette may then be coated with a reflective substance so as to increaseinternal reflection. For example, “silvering” is a chemical process ofcoating glass with a reflective substance. In this process, the pipettemay be sputtered with powdered aluminum by placing it in a vacuumchamber with electrically heated nichrome coils which sublime thealuminum. When subsequently exposed to oxygen in an oven, a layer ofdurable, transparent aluminum oxide is formed.

An index-matching material may be used within the pipette and around theLED lens so as to smooth or eliminate the transition in refractiveindices between the LED lens and the lumen of the pipette material byeliminating air space and approximating the refractive indices the lensmaterials. Index-matching liquids and materials are commerciallymanufactured and sold by many sources including Timbercon, Inc., LakeOswego, Oreg. The index of refraction of various translucent andtransparent materials, such as LED lenses, is generally available aspart of a manufacturers specification or various publicly availablelists/databases. Another consideration is the particular wavelength(s)of light to be used as this can affect the index of refraction.

The present invention may also be used for precisely delivering light tospecific target regions of the body for other phototherapy purposes. Forexample, some wavelengths of light are known to have bactericidalproperties, while other wavelengths may induce the production of certaindesired molecular products.

The various embodiments described above are provided by way ofillustration only and should not be construed to limit the invention.Based on the above discussion and illustrations, those skilled in theart will readily recognize that various modifications and changes may bemade to the present invention without strictly following the exemplaryembodiments and applications illustrated and described herein. Forinstance, such changes may include the use of digital logic ormicroprocessors to control the emitted light. Such modifications andchanges do not depart from the true spirit and scope of the presentinvention, which is set forth in the following claims.

What is claimed is:
 1. A device for delivering light in vivo in apatient, the device comprising: an implantable optical delivery deviceconfigured for placement under the skin of the patient; a light sourcefor producing light from electrical power; an optical transmissionelement made from a material that is transparent to the light from thelight source, the material having an elongated shape that substantiallyencases the light source at a proximal end and that is for deliveringthe light from the light source to a distal end within the brain of thepatient, wherein a distal tip of the optical transmission element isadapted for rotation about the longitudinal axis to change the positionof the distal tip along the longitudinal axis; a fixation portionphysically coupled to the optical transmission element and configured toattach the optical transmission element to the skull of the patient,wherein the fixation portion is physically coupled to a proximal end ofthe optical transmission element, and wherein the optical transmissionelement is configured to emit light from the distal end of the opticaltransmission element; and a heat dissipation portion having a thermallyconductive path for removing heat from near the light source.
 2. Thedevice of claim 1, wherein the optical transmission element defines alumen and wherein the material is one of glass and plastic.
 3. Thedevice of claim 2, wherein the lumen contains a substance having anindex of refraction that is the same as the material of the elementdefining the lumen.
 4. The device of claim 1, wherein the opticaltransmission element is rigid along a direction of transmission for thelight.
 5. The device of claim 4, wherein the optical transmissionelement includes an outer layer of a second material that facilitateslight traveling along the direction of transmission.
 6. The device ofclaim 1, further including a temperature sensor for sensing atemperature near the optical transmission element and a control circuitfor controlling the activation of the light source in response to thesensed temperature.
 7. The device of claim 1, wherein the opticaltransmission element is configured to direct light along a longitudinalaxis that extends from the proximal end to the distal and wherein theoptical transmission element is configured and arranged to direct lightleaving the transmission element at a non-zero angle relative to thelongitudinal axis.
 8. The device of claim 7, wherein the fixationportion is configured and arranged to allow rotational movement, aboutthe longitudinal axis, of the optical transmission element duringimplantation and to prevent the rotational movement after implantation.9. The device of claim 1, wherein the material of optical transmissionelement is glass that is coated with a reflective substance.
 10. Thedevice of claim 1, further including an implantable signal source havinga power supply, a control circuit for generating electrical signals thatactivate the light source and conductors for transmitting the electricalsignals to the light source.
 11. The device of claim 10, wherein theimplantable signal source is designed for placement within the chestcavity in connection with the optical transmission element beingimplanted within the brain.
 12. The device of claim 1, further includingan implantable signal source configured to provide signals to the lightsource that generate light pulses of sufficient rate and intensity tocontrol individual action potentials.
 13. The device of claim 1, whereinthe optical transmission element is configured to provide total internalreflection of light from the light source by using internal bodycomponents as cladding that increases a critical angle of reflection forthe optical transmission element.
 14. The device of claim 1, wherein thefixation portion comprises a fixation base that is configured to beaffixed to the skull of the patient.
 15. The device of claim 14, whereinthe fixation base is configured to be affixed to the skull of thepatient by suturing or cementing the fixation base to the skull of thepatient.